In the past ten years, advances in biotechnology have made it possible to identify, develop and produce a variety of antibodies for use in the diagnosis, prevention, and treatment of many different diseases and disorders. Examples of such antibodies are the anti-rabies virus antibodies described in WO 2005/118644. An antibody cocktail with two such antibodies, CR57 and CR4098, is particularly advantageous and can be used in rabies post-exposure prophylaxis. In WO 2005/118644, these antibodies were prepared and used in PBS.
Like any protein, the biological activity of an antibody, such as its binding affinity or neutralizing activity, depends upon the conformational integrity of at least a core sequence of amino acids remaining intact while protecting the protein's multiple functional groups from degradation. Chemical and physical instability can each contribute to degradation of an antibody. Because antibodies are larger and more complex than traditional organic and inorganic drugs, the formulation of such antibodies poses special problems. Antibody stability can be affected by such factors as ionic strength, pH, temperature, repeated cycles of freeze/thaw, antibody concentration and shear forces. Active antibodies may be lost as a result of physical instabilities, including denaturation, aggregation (both soluble and insoluble aggregate formation), precipitation and adsorption as well as chemical instabilities, including, for example, racemization, beta-elimination or disulfide exchange, hydrolysis, deamidation, and oxidation, to name just a few. Any of these instabilities can potentially result in the formation of antibody by-products or derivatives having lowered biological activity, increased toxicity, and/or increased immunogenicity.
While the prior art indicates numerous examples of excipients that can be suitably employed to create antibody formulations for specific antibodies, it is impossible to predict which excipients should be added and in what amount they should be added to overcome the particular instability problems that a particular antibody may have. Furthermore, it is difficult to find optimal conditions, such as antibody concentration, pH and storage temperature, that keep a particular antibody chemically and biologically stable within a particular formulation. In view of all the factors that can be varied, finding suitable excipients and optimal conditions for formulating a single monoclonal antibody is fraught with challenges. Obviously, finding suitable excipients and optimal conditions for formulating two different monoclonal antibodies in a single formulation is even more difficult and problematic. Notably, the art does not provide a long-term stable pharmaceutical preparation containing two different recombinant monoclonal antibodies.
Accordingly, there existed a need in the art to find formulations wherein not only a single monoclonal antibody, but even two different specific monoclonal antibodies against rabies virus, are stable on storage over a prolonged period of time. The storage stability should also be retained in the case of shear forces acting during transport and under modified climatic conditions, in particular at elevated temperature and atmospheric humidity. Furthermore, the formulation should be suitable for the intended route of administration, should be well tolerated and should have a simple structure.
It is an object of the invention to provide such formulations.